This U54 Center will use translational research as a tool for medication development in cocaine use disorder (CocUD).The overall goal of Project 3 is to assess novel compounds in cocaine self-administration and cue reactivity models to provide key preclinical profiles of potential therapeutics for CocUD. This information is necessary to design future human studies to assess abstinence induction in active users of cocaine or relapse prevention in abstinent subjects. The initial compound to be studied in Project 3 will be pimavanserin, a selective 5-HT2AR antagonist which also displays inverse agonist activity in functional assays. Preclinical studies have demonstrated that selective 5-HT2AR antagonist/inverse agonists (e.g., M100907) consistently reduce both cue- and cocaine-evoked reinstatement in cocaine self-administration assays in animals. Given that pimavanserin is on track for potential approval by the U.S. Food and Drug Administration for use in the treatment of psychosis during Parkinson's disease, the ultimate availability of this novel medication will allow future evaluation for suppression of relapse in human subjects. Project 3 will employ a portfolio of validated animal models for CocUD to develop a comprehensive preclinical profile of pimavanserin prior to human studies, including assessment of the efficacy of acute and chronic pimavanserin in preclinical models of cocaine intake (fixed and progressive ratio self-administration) and cue reactivity (attentional orientation toward drug-associated cues). In addition, our research has demonstrated that a selective 5-HT2AR antagonist plus a selective 5-HT2cR agonist evoke synergistic suppression in preclinical models of CocUD, and combinatorial treatment with lorcaserin plus pimavanserin will be the second medication to be assessed. Finally, we present evidence that high impulsive action (rapid response impulsivity) predicts high cue reactivity as measured by attentional bias toward cocaine-associated cues in cocaine-dependent human subjects and in rats. For this reason, as an exploratory aim, we will assess the impact of impulsivity on the response to pimavanserin as well as pimavanserin plus lorcaserin. These translational approaches will provide a cohesive dataset to support the novel pharmacotherapeutic prospect that pimavanserin alone or in combination with lorcaserin may support behavioral recovery in CocUD.